Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity.
Joachim HannaFlavio BekeLouise M O'BrienChrysa KapeniHung-Chang ChenValentina CarbonaroAlexander Byungsuk KimKamal KishoreTimon Erik AdolphMikkel-Ole SkjoedtKarsten SkjoedtMarc de la RocheMaike de la RochePublished in: Nature communications (2022)
Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell fate decisions during embryogenesis and adult tissue patterning. Here we find that cell-autonomous Hedgehog signaling, independent of exogenous ligands, selectively drives the polarization of Th17 cells but not other T helper cell subsets. We show that endogenous Hedgehog ligand, Ihh, signals to activate both canonical and non-canonical Hedgehog pathways through Gli3 and AMPK. We demonstrate that Hedgehog pathway inhibition with either the clinically-approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4 + T cells greatly diminishes disease severity in two mouse models of intestinal inflammation. We confirm that Hedgehog pathway expression is upregulated in tissue from human ulcerative colitis patients and correlates with Th17 marker expression. This work implicates Hedgehog signaling in Th17 polarization and intestinal immunopathology and indicates the potential therapeutic use of Hedgehog inhibitors in the treatment of inflammatory bowel disease.
Keyphrases
- induced apoptosis
- small molecule
- single cell
- poor prognosis
- cell fate
- cell therapy
- ulcerative colitis
- oxidative stress
- end stage renal disease
- signaling pathway
- stem cells
- multiple sclerosis
- newly diagnosed
- epithelial mesenchymal transition
- chronic kidney disease
- dendritic cells
- dna methylation
- escherichia coli
- cell death
- transcription factor
- endoplasmic reticulum stress
- gene expression
- peritoneal dialysis
- mesenchymal stem cells
- basal cell carcinoma
- replacement therapy
- smoking cessation